The obesity pandemic predisposes millions to develop type-2 diabetes. Development of therapies for obesity, however, has been limited by incomplete understanding of the neuronal circuits that control energy balance. The lateral hypothalamic area (LHA) coordinates diverse physiologic stimuli with appropriate adaptive behaviors (including feeding, drinking and locomotor behavior) to modulate body weight. Many LHA neurons express the anorectic neuropeptide neurotensin (Nts) and are activated by stimuli that suppress feeding and promote locomotor activity, including dehydration, inflammation and the hormone leptin. These cue-activated LHA Nts neurons project into the midbrain, where Nts has been shown to activate dopamine (DA) neurons, decrease feeding and increase locomotor activity. I hypothesize that LHA Nts neurons coordinate anorectic signals and the mesolimbic dopamine system to promote weight loss, and loss of action via these neurons promotes obesity. In Aim 1 I will selectively ablate LHA Nts neurons to define their requirement for coordinating energy balance. In Aim 2 I will determine the neural mechanisms by which subpopulations of LHA Nts neurons transduce anorectic cues to the midbrain. To accomplish these aims my Sponsor, Dr. Gina Leinninger, will train me to use novel genetic reagents and metabolic phenotyping to examine the pathogenesis of obesity. My Co-Sponsor, Dr. James Galligan will train me in paradigms to determine how inflammatory signaling regulates LHA Nts neurons and contributes to energy balance. Collectively, their training in state-of-the art techniques bridging neuroscience, toxicology and metabolism will enable me to complete these studies and develop into a productive, independent researcher studying obesity.